d-Lysergic acid diethylamide has major potential as a cognitive enhancer

Abstract

Psychedelic agonists of serotonin receptors induce neural plasticity and synaptogenesis, but their potential to enhance learning remains uncharted. Here we show that a single dose of d-LSD, a potent serotonergic agonist, increased novel object preference in young and adult rats several days after treatment. d-LSD alone did not increase preference in old animals, but could rescue it to young levels when followed by a 6-day exposure to enriched environment (EE).Mass spectrometry-based proteomics in human brain organoids treated with d-LSD showed upregulation of proteins from the presynaptic active zone. A computational model of synaptic connectivity in the hippocampus and prefrontal cortex suggests that d-LSD enhances novelty preference by combining local synaptic changes in mnemonic and executive regions, with alterations of longrange synapses. Better pattern separation within EE explained its synergy with d-LSD in rescuing novelty preference in old animals. These results advance the use of d-LSD in cognitive enhancement.

Repeated lysergic acid diethylamide (LSD) reverses stress-induced anxiety-like behavior, cortical synaptogenesis deficits and serotonergic neurotransmission decline

“…BDNF-induced glutamate release has been shown to decrease following chronic restraint stress, together with glucocorticoid receptor expression [52]. In line with the current findings, LSD increased synaptic plasticity in brain organoids, an effect accompanied by increased expression of proteins involved in synaptogenesis and plasticity, such as synaptophysin, glutamate metabotropic receptor 7, and synaptic vesicle glycoprotein 2A [62]. LSD shares with antidepressants not only the capacity to increase the density of apical dendritic spines in the mPFC [57], which is hypothesized to endure antidepressant effects but also the capacity to potentiate the 5-HT neurotransmission.…”

Psychedelics as a Treatment for Alzheimer’s Disease Dementia

“…In rat models, 5HT2A-R activation with mid-dose psilocybin (0.13 mg/kg) enhances both prospective and retrospective learning with lesser effects at low-dose (0.06 mg/kg; Buchborn et al, 2014 ; Cini et al, 2019 ). Consecutive daily dosing diminished benefits, and older rodents learning was enhanced by an enriched environment (Buchborn et al, 2014 ).…”

Psychedelics, Sociality, and Human Evolution

“…The presence of psychedelics in the early human diet may have also favored positive selection for exaggerated cortical plasticity – which apparently is a uniquely human derivation ( Krubitzer, 2009 ) – and for the expansion of key functional networks involved in the enhancement of cognitive functions in humans compared to other primate species. Through their agonist action at 5-HT 2A receptors, psychedelics elevate synaptic efficacy and neuroplasticity ( Ly et al, 2018 ) and functionally modulate the activity and connectivity of the frontoparietal network and the DMN ( Carhart-Harris and Friston, 2019 ; Vollenweider and Preller, 2020 ), enhancing (potentially in the long-term) cognitive functioning ( Cini et al, 2019 ) and sociality ( Preller and Vollenweider, 2019 ). It has also been shown that psychedelic effects can reduce symptoms of autism ( Sigafoos et al, 2007 ) and mimic certain aspects of psychosis ( Carhart-Harris et al, 2016a ).…”